Cellular damage due to oxidative stress caused by reactive oxygen species (ROS) has been demonstrated to be involved in the onset or progression of various chronic diseases, e.g., cardiovascular disease, including arteriosclerosis and hypertension; diabetes and diabetic related complications, such as glomerular nephropathy; cerebral nerve degenerative diseases, such as Alzheimer's disease, Parkinson's disease, ALS (amyotrophic lateral sclerosis) and multiple sclerosis; asthma, chronic obstructive pulmonary disease, skin diseases, eye diseases, and cancer. Enhancing the capability of protecting from oxidative stress may be useful in treating these diseases. Further, with the varied etiology associated with this diverse set of diseases, a general strategy to mitigate oxidative stress would be beneficial.
The basic biochemistry of a cell generates ROS, including superoxide anions, hydroxyl anions, nitric oxide, peroxynitrite, and hydrogen peroxide. All of these products serve critical cellular signaling needs, but also have deleterious effects if overproduced or left unchecked. Many disease conditions induce persistent levels of ROS that are associated with the establishment of chronic pathophysiologic changes seen within a variety of tissues. These complications, in and of themselves, may be the primary drivers of disease morbidity and mortality.
Under normal physiological conditions, production of ROS are counterbalanced by a well defined and conserved set of cellular pathways that respond to, limit, and repair the damage due to ROS. This adaptive program is largely controlled by two proteins: Kelch like-ECH-associated protein 1 (Keap1) and the transcription factor NFEL2L2 (Nrf2). The Keap1-Nrf2 system has evolved to respond to intracellular oxidative stress; in particular the generation of reactive electrophiles produced from oxidation of endogenous cellular constituents as well as xenobiotics. In the absence of cellular oxidative stress, Nrf2 levels in the cytoplasm are maintained at low basal levels by binding to Keap1 and Cullin 3, which leads to the degradation of Nrf2 by ubiquitination. During periods of oxidative stress, as levels of reactive electrophilic metabolites increase, the ability of Keap1 to target Nrf2 for ubiquitin-dependent degradation is disrupted, thereby increasing Nrf2 protein levels and its transport into the nucleus, resulting in transcription of antioxidant response genes. Nrf2 binds to antioxidant response elements (AREs) found in the promoters of over 200 anti-oxidant and cytoprotective genes including NAD(P)H dehydrogenase, quinone 1 (NQO1), catalase (CAT), glutamate-cysteine ligase (GCLC), aldoketoreductase family members, thioredoxin reductase (TXNRD1), and heme oxygenase-1 (HMOX1). Activation of the anti-oxidant response via the Keap1-Nrf2 pathway is considered to be protective in nearly every organ system. As described below, various Nrf2 Activators have been and are being developed for treatment of diseases or conditions associated with oxidative stress.
There is, however, another mechanism by which ARE-regulated genes are controlled and that is through Bach1, a transcriptional repressor that binds to ARE promoter elements. Binding of Bach1 to ARE promoter elements results in suppression of Nrf2 activity. Bach1 regulates ARE gene expression by binding to the small Maf proteins and ARE sequences that are also separately bound by Nrf2. Natively, Bach1 may be bound by its ligand, heme, which causes Bach1 to be displaced from the ARE, exported from the nucleus, and degraded. Bach1 and its ligand coordinate the overall intracellular levels of heme and iron with anti-oxidant gene expression. Genetic evidence indicates that Bach1 deletion leads to a significant level of protection in a wide variety of murine disease models. These observations suggest that ARE-regulated genes may be controlled by an intracellular ligand independent of ROS generation, electrophilic reactivity, or elevation of Nrf2 levels in the cell. Thus, agents that target Bach1 and inhibit Bach1 repression may be useful to elevate expression of ARE-regulated genes.
PCT Publication No. WO 2011/103018 (“WO '018”) describes substituted fused imidazole derivatives that upregulate expression of HMOX1 in vitro. PCT Publication No. WO 2012/094580 (“WO '580”) describes various compounds that modulate cellular oxidative stress including fused imidazole derivatives having a structure similar to or the same as compounds disclosed in WO '018. Paragraphs [0196] to [0198] of WO '580 describe tests that suggest that fused imidazole derivatives similar to those disclosed in WO '018 may directly modulate Bach1 activity so as to inhibit Bach 1's repression of Nrf2 dependent gene transcription.